Exercise training (EX) increases coronary blood flow capacity and alters coronary vasomotor responsiveness[unreadable] in normal animals. Endothelium-dependent dilation (EDO) is blunted in the left anterior descending coronary[unreadable] artery (LAD) of sedentary pigs (SED) with early stage coronary artery disease (CAD) produced by feeding a high[unreadable] fat/cholesterol diet for 5 months (HFC). EX of this HFC model of CAD restores EDO in the LAD. These[unreadable] interactive effects of EX and HFC diet form the foundation for the central hypothesis of Project 3: The beneficial[unreadable] effects of EX in prevention and treatment of CAD are mediated by restoration/maintenance of a normal[unreadable] coronary endothelialphenotype. Aim 1 will determine mechanisms responsible for EX-induced improvements[unreadable] in EDO of LADs of HFC pigs. Preliminary results indicate that EX preserves/restores EDO in HFC pigs by[unreadable] increasing availability of endothelium-derived NO and decreasing production of a cyclooxygenase constrictor[unreadable] substance. We will use pharmacological, biochemical and molecular approaches to determine whether these[unreadable] modifications result from altered expression of genes for enzymes/receptors responsible for EDO and/or altered[unreadable] activity of these enzymes. Aim 2 will determine whether mechanical signals (shear stress and stretch) produce[unreadable] EX like changes in expression of endothelial nitric oxide synthase (eNOS) and other protective genes in normal[unreadable] and diseased coronary arteries. In Aim 3 we will determine whether EX produces a more atheroprotective[unreadable] phenotype of endothelial and/or foam cells during early development of CAD. We will use biochemical,[unreadable] molecular and morphologic approaches to characterize the phenotypes of vascular cells in SED and EX arteries.[unreadable] Aim 4 experiments are designed to use genetically modified pigs (that over express eNOS and eNOS knock-out)[unreadable] to determine the role of eNOS in the interactive effects of EX and HFC on endothelial function and CAD.[unreadable] Available results indicate that much of the beneficial effects of EX on CAD are mediated by changes in NO[unreadable] release from eNOS. Aim 5 will use the protocols and techniques applied to our model of early CAD to test the[unreadable] hypothesis that EX also has beneficial effects on more advanced disease (2 yrs on the HFC diet). Completion[unreadable] of the research proposed in Project 3 will improve understanding of mechanisms for anti-atherogenic effects[unreadable] of EX on endothelial function and phenotype in coronary arteries and the roles of inflamation, shear stress, and[unreadable] distention in producing or sustaining an anti-atherogenic phenotype of endothelial and foam cells in the arterial[unreadable] wall. This research will provide a solid fundamental basis for understanding the effects of EX in[unreadable] preventing/reversing CAD and for an improved ability to use exercise in treating and prevention of CAD.